Research Projects

Centrosome amplification (CA) is a striking hallmark of numerous cancers, including solid tumors and it is caused due to its aggravated centrosome duplication and maturation cycles. In quiescent stage, centrosome, specifically its mother centriole in the form of basal body makes primary cilia and presence of cilia inhibits centrosome duplication and cell cycle entry. Cancer cells of diverse tissue origins are found to loose cilia primarily by disassembling their inner microtubule skeleton; and the transition of ciliary state to the proliferation-promoting duplication state of centrosome has been implicated in tumorigenesis. However, the underlying mechanisms remain largely unclear. Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) is a centrosome protein that is over-expressed in many cancers and promotes cancer cell growth. Our preliminary data reveal marked reduction of TACC3 level when cells are in ciliary state. Our analysis also indicate that E3 ubiquitin ligase FBXW7 regulates the stability of TACC3. It is also observed that depletion of TACC3 increases the level of microtubule acetylation, which promotes cilia assembly. In this proposal, I aim to investigate how FBXW7-mediated TACC3 regulation is molecularly linked to cilia assembly/disassembly and centrosome duplication/maturation and uncover how such regulation is associated with histone deacetylase 6 (HDAC6)-mediated ciliary microtubule disassembly and upregulates centrosome duplication and maturation. The study is expected to unravel the molecular mechanism underlying cilia to centrosome transition in tumor cells and facilitate in identifying novel drug targets against human cancers.